Remedies for psychoneurosis

ABSTRACT

A therapeutic drug for psychoneurotic disorders, which is useful for therapies of psychoneurotic disorders, especially restless legs syndrome is disclosed. The therapeutic drug for psychoneurotic disorders according to the present invention comprises as an effective ingredient an opioid κ receptor agonist compound (excluding pentazocine) such as (−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloric acid salt.

TECHNICAL FIELD

[0001] The present invention relates to a therapeutic drug forpsychoneurotic disorders. The therapeutic drug for psychoneuroticdisorders according to the present invention are useful for therapies ofpsychoneurotic disorders such as restless legs syndrome (hereinafteralso referred to as “RLS”).

BACKGROUND ART

[0002] RLS is a nervous system disorder, which is thought to be one ofthe peripheral neuropathies, which gives very uncomfortable abnormalsensation that is a strong itchy sensation on the lower limbs at rest orwhen falling asleep. Although in some cases, the itchy sensation is alsofelt on the upper limbs or the trunk, the disorder is characterized bythe strong abnormal sensation on the lower limbs as expressed in itsname. If RLS is once started, it is impossible to keep the legs stilland the patient chafes the soles or moves the legs in order to try toalleviate the symptom even in the slightest degree. In severe cases, thepatient cannot keep still on the bed, so that the patient stands up andwalks around. Such uncomfortable sensation on the lower limbs cannot beappreciated by those who have not experienced it. According to thecomplaints by patients themselves, the sensation is often expresses as“itchy” or “as if ants are creeping” (formication). Since RLS oftenoccurs in the night when the patient is falling asleep, the patientscannot keep still, and the falling asleep or the falling asleep in thesecond time after intermediate awakening is disturbed, so that thepatients suffer from severe insomnia. Due to the chronic shortage ofsleep, the patients are tired and may suffer from strong fret. Reportedpathological states which cause RLS include anemia (iron deficiencyanemia), renal failure, uremia, gastrectomy, pregnancy, metabolicdiseases (diabetes, porphyria, gout, amyloidosis and the like),infectious diseases (tuberculosis, pneumonia, hepatitis, poliomyelitisand the like), venous thrombosis in lower limbs, drugs (promethazine,prochlorperazine, barbiturates and the like), coldness and psychicfactors (Zenji SHIOZAWA et al., Journal of New Remedies & Clinics,Vol.49, 218-255, 2000).

[0003] As the cause of RLS, the publication (NIH Publication No.00-3788, March 2000) by U.S. National Institute of Health (NIH) suggestssecondary onset accompanying the above-mentioned pathological states andfamilial genetic factors as well as drugs such as tricyclicantidepressants, selective serotonin resorption inhibitors (SSRIs),lithium, dopamine antagonists and caffeine.

[0004] Although no survey has been carried out, which precisely measuresprevalence of RLS, the prevalence of RLS is estimated to be 2 to 15% inthe U.S. based on the total population (NIH Publication No. 00-3788) or3 to 8% (publication in Japanese by the U.S. RLS Foundation, 1999), 1 to5% in Europe and 1 to 3% in Japan (Yuichi INOUE et al., Journal of NewRemedies & Clinics, Vol.49, 244-255, 2000). When classified according tothe pathological states, the prevalence in the patients suffering fromrenal failure is extremely high, and is estimated to be about 50% inboth the U.S. and Japan (Isao EGAWA et al., New Remedies & Clinics,Vol.49, 230-235, 2000). RLS is one of the major causes which impairquality of life of the patients. Those which are thought to be symptomsor disorders similar to RLS include periodic limb movements, PLM),myoclonic syndrome, contraction and painful contraction.

[0005] Since the cause of RLS has not been well clarified, radicaltherapy thereof has not been established. In the U.S., there is no drugwhich was approved by FDA for use against RLS. Although variouschemotherapies are now being tried, including those using dopamineagonist, opioid (opioid μ receptor agonist), benzodiazepine,anticonvulsants and the like, they have problems in that theeffectiveness is insufficient, sleepiness is carried over until themorning or the effectiveness is reduced with continuous use, so thatnone of them has been established as a therapeutic method. Opioid drugswhich have been applied to RLS include opioid μ receptor agonists suchas codeine, hydrocodeine, oxycodone, propoxyphene, tramadol andmethadone, and pentazocine which is an opioid μ and κ receptor agonist.However, all of them have insufficient effectivities and problems ofside effects or dependency, so that medical satisfactions thereof arepoor (NIH Publication No. 00-3788; publication in English by the U.S.RLS Foundation, 2000, Pentagin: U.S. Pat. No. 6,114,326).

[0006] In the U.S., RLS Research Foundation was founded. It enlightensthe correct understanding of the disease and hints on the life, andsupports the research for therapeutic methods.

[0007] Thus, in spite of the fact that RLS is very uncomfortable to thepatients and decreases the quality of life, the cause thereof has notbeen clarified and effective therapeutic method has not beenestablished. Thus, RLS is a big problem in medicine and development ofmore useful therapeutic method is strongly demanded.

DISCLOSURE OF THE INVENTION

[0008] An object of the present invention is to provide a therapeuticdrug for psychoneurotic disorders, which is useful for the therapies ofnervous diseases, especially restless legs syndrome.

[0009] The present inventors intensively studied for attaining theabove-mentioned object to discover that opioid κ receptor agonistcompounds are useful for the therapies of nervous diseases, especiallyrestless legs syndrome, thereby completing the present invention.

[0010] That is, the present invention provides a therapeutic drug forpsychoneurotic disorders comprising an opioid κ receptor agonistcompound (excluding pentazocine) as an effective ingredient. The presentinvention also provides a use of an opioid κ receptor agonist compound(excluding pentazocine) for the production of a therapeutic drug forpsychoneurotic disorders. The present invention further provides amethod of therapy for psychoneurotic disorders, comprising administeringan effective amount of an opioid κ receptor agonist compound (excludingpentazocine).

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] The opioid κ receptor agonist compound according to the presentinvention includes compounds which exhibit affinities to κ receptorirrespective of chemical structural specificity. Those which are moreselective to κ receptor than to μ and δ receptors are preferred. Moreparticularly, preferred examples thereof include those represented byFormula (I):

[0012] [wherein . . . represents double bond or single bond; R¹represents C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl,C₆-C₁₂ aryl, C₇-C₁₃ aralkyl, C₄-C₇ alkenyl, allyl, C₁-C₅furan-2-yl-alkyl or C₁-C₅ thiophene-2-yl-alkyl; R² represents hydrogen,hydroxy, nitro, C₁-C₅ alkanoyloxy, C₁-C₅ alkoxy, C₁-C₅ alkyl or —NR⁹R¹⁰wherein R⁹ represents hydrogen or C₁-C₅ alkyl, and R¹⁰ representshydrogen, C₁-C₅ alkyl or —C(═O)R¹¹— wherein R¹¹ represents hydrogen,phenyl or C₁-C₅ alkyl; R³ represents hydrogen, hydroxy, C₁-C₅alkanoyloxy or C₁-C₅ alkoxy; A represents —XC(═Y)—, —XC(═Y)Z-, —X— or—XSO₂— (wherein X, Y and Z independently represent NR⁴, S or O; R⁴represents hydrogen, C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl,wherein R⁴s may be the same or different); B represents valence bond,C₁-C₁₄ linear or branched alkylene (with the proviso that said alkylenemay have at least one substituent selected from the group consisting ofC₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine,iodine, amino, nitro, cyano, trifluoromethyl and phenoxy, and that 1 to3 methylene groups may be substituted by carbonyl group(s)), C₂-C₁₄linear or branched acyclic unsaturated hydrocarbon containing 1 to 3double bonds and/or triple bonds (with the proviso that said acyclicunsaturated hydrocarbon may have at least one substituent selected fromthe group consisting of C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy,fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl and phenoxy, and that 1 to 3 methylene groups may besubstituted by carbonyl group(s)), or C₁-C₁₄ linear or branchedsaturated or unsaturated hydrocarbon containing 1 to 5 thioether bonds,ether bonds and/or amino bonds (with the proviso that hetero atom doesnot directly bind to A, and 1 to 3 methylene groups may be substitutedby carbonyl group(s)); R⁵ represents hydrogen or an organic group havingone of the following skeletons:

[0013] (wherein Q represents —NH—, —O— or —S—; T represents —CH₂—, —NH—,—S— or —O—; 1 represents an integer of 0 to 5; and m and n independentlyrepresent integers of not less than 0, the sum of m and n being not morethan 5)

[0014] (with the proviso that the skeletons may have at least onesubstituent selected from the group consisting of C₁-C₅ alkyl, C₁-C₅alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine,amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxyand methylenedioxy); R⁶ represents hydrogen; R⁷ represents hydrogen,hydroxy, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, or R⁶ and R⁷ cooperativelyrepresent —O—, —CH₂— or —S—; and R⁸ represents hydrogen, C₁-C₅ alkyl orC₁-C₅ alkanoyl; said Formula (I) includes (+) isomer, (−) isomer and (±)isomer] and pharmaceutically acceptable acid addition salts thereof.

[0015] In the case of a group such as “alkyl” or “alkoxy”, wherein thereare linear and branched types, both linear and branched groups areincluded in the present specification unless otherwise specified. In thedefinition of R⁵ in the above-described Formula (I), the term “anorganic group having a skeleton” means a monovalent group formed byelimination of one hydrogen atom from the ring constituting therespective compound shown as the above-mentioned skeleton or the thusformed monovalent group having the above-mentioned substituent(s).

[0016] In the compounds represented by Formula (I), preferred examplesof R include C₁-C₅ alkyl, C₄-C₇ cycloalkylmethyl, C₅-C₇cycloalkenylmethyl, C₇-C₁₃ phenylalkyl, C₄-C₇ alkenyl, allyl, C₁-C₅furan-2-yl-alkyl and C₁-C₅ thiophene-2-yl-alkyl. Among these, methyl,ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl,phenethyl, furan-2-yl-methyl and thiophene-2-yl-methyl are preferred.

[0017] Preferred examples of R² include hydrogen, hydroxy, nitro,acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino,acetylamino and benzoylamino. Among these, hydrogen, hydroxy, nitro,acetoxy, methoxy, methyl and dimethylamino, especially, hydrogen,hydroxy, acetoxy and methoxy, are preferred.

[0018] As R³, hydrogen, hydroxy, acetoxy and methoxy are preferred,especially, hydroxy, acetoxy and methoxy are preferred.

[0019] Preferred concrete examples of A include —NR⁴C(═O)—, —NR⁴C(═S)—,—NR⁴C(═O)O—, —NR⁴C(═O)NR⁴—, —NR⁴C(═S)NR⁴—, —NR⁴C(═O)S—, —OC(═O)—,—OC(═O)O—, —SC(═O)—, —NR⁴—, —O—, —NR⁴SO₂— and —OSO₂—. Among these,—NR⁴C(═O)—, —NR⁴C(═S)—, —NR⁴C(═O)O—, —NR⁴C(═O)NR⁴—, —NR⁴C(═S)NR⁴— and—NR⁴SO₂— are preferred. As the R⁴, hydrogen and C₁-C₅ linear or branchedalkyl are preferred. Particularly, C₁-C₅ linear or branched alkyl,especially, methyl, ethyl, propyl, butyl and isobutyl are preferred.Among those mentioned above, —XC(═Y)— (wherein X represents NR⁴, S or O;Y represents O; and R⁴ represents hydrogen or C₁-C₅ alkyl), —XC(═Y)Z-,—X—, —XSO₂— (wherein X represents NR⁴; Y represents O or S; Z representsNR⁴ or O; and R⁴ represents hydrogen or C₁-C₅ alkyl), —XC(═Y)— and—XC(═Y)Z- (wherein X represents NR⁴, Y represents O, Z represents O andR⁴ represents C₁-C₅ alkyl) are preferred. Especially, —XC(═Y)— (whereinX represents NR⁴, Y represents O and R⁴ represents C₁-C₅ alkyl) arepreferred.

[0020] Preferred examples of B include —(CH₂)_(n)— (n=0-10),—(CH₂)_(n)—C(═O)— (n=1-4), —CH═CH—(CH₂)_(n)— (n=0-4), —C≡C—(CH₂)_(n)—(n=0-4), —CH₂—O—, —CH₂—S—, —(CH₂)₂—O—CH₂— and —CH═CH—CH═CH—(CH₂)_(n)—(n=0-4), especially —(CH₂)_(n)— (n=1-3), —CH═CH—(CH₂)_(n)— (n=0-4),—C≡C—(CH₂)_(n)— (n=0-4), —CH₂—O— and —CH₂—S—. Among these, C₁-C₃ linearalkylene, —CH═CH—, —C≡C—, —CH₂O— and —CH₂S—, especially, —CH═CH— and—C—C, are more preferred (needless to say, these preferred examplesinclude those having the above-mentioned various substituents).

[0021] As the R⁵, hydrogen and the organic groups having one of thefollowing skeletons are preferred:

[0022] (wherein the definitions of Q, T, l, m and n are the same asdescribed above),

[0023] (with the proviso that the organic groups may have at least onesubstituent selected from the group consisting of C₁-C₅ alkyl, C₁-C₅alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine, amino,nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy andmethylenedioxy).

[0024] Among the above-described R⁵, preferred are hydrogen, phenyl,thienyl and furanyl (with the proviso that these organic groups may haveat least one substituent selected from the group consisting of C₁-C₅alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine,bromine, amino, nitro, cyano, isothiocyanato, trifluoromethyl,trifluoromethoxy and methylenedioxy).

[0025] More specific preferred examples include hydrogen, phenyl,4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl,3,4-dimethoxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl,3,4-dihydroxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl,3,4-difluorophenyl, perfluorophenyl, 4-chlorophenyl, 3-chlorophenyl,2-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl,3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,2-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 2-aminophenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3,4-methylenedioxyphenyl, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl,cyclopentyl and cyclohexyl. Needless to say, however, R⁵ is notrestricted to these groups.

[0026] The opioid κ receptor agonist compounds represented by Formula(I) may be produced by the method described in Japanese Patent No.2525552.

[0027] Preferred examples of opioid κ receptor agonist compound includethe compounds represented by the following Formula (II):

[0028] [wherein R represents two hydrogen atoms or —O—CH₂CH₂CH₂—; Arrepresents

[0029] (wherein X and Y independently represent hydrogen or chlorine) or

[0030] (wherein Z represents O or S);

[0031] said Formula (II) includes (+) isomer, (−) isomer and (±) isomer]

[0032] and pharmaceutically acceptable acid addition salts thereof.

[0033] Among the compounds represented by Formula (II),trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide,trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide,(5β,7β,8α)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzene acetamide,(5β,7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide, and(5β,7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzene acetamide are preferred.

[0034] The opioid κ receptor agonist compounds represented by Formula(II) may be produced by the methods described in J. Szmuszkovicz et al.,J. Med. Chem., 25, 1125(1982); D. C. Horwell et al., U.S. Pat. No.5,587,37(1983); J. Szmuszkovicz et al., Eur. Patent Appl. EP126612(1984); and P. R. Halfpenny, D. C. Horwell et al., J. Med. Chem., 33,286 (1990).

[0035] Preferred examples of opioid κ receptor agonist compound alsoinclude the compounds represented by the following Formula (III):

[0036] [wherein X represents hydrogen, chlorine or trifluoromethyl; Yrepresents hydrogen or chlorine; and Z represents —CH₂—, —OCH₂ CH₂O— or═NCO₂ CH₃; said Formula (III) includes (+) isomer, (−) isomer and (±)isomer]

[0037] and pharmaceutically acceptable acid addition salts thereof.

[0038] Among the compounds represented by Formula (III), methyl4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate,1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine,1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine and1-[(3,4-dichlorophenyl)acetyl]-4,4-ethylenedioxy-2-[(1-pyrrolidinyl)methyl]piperidineare preferred.

[0039] The opioid κ receptor agonist compounds represented by Formula(III) may be produced by the methods described in A. Naylor et al., J.Med. Chem., 36, 2075 (1993); V. Vecchietti et al., J. Med. Chem., 34,397 (1991), ibid. Eur. Patent Appl. EP232,612 (1987); EP260,041 (1988);EP275,696 (1988); and D. I. C. Scopes et al., J. Med. Chem., 35, 490(1992).

[0040] Preferred examples of opioid κ receptor agonist compound stillalso include the compounds represented by the following Formula (IV):

[0041] [wherein X and Y independently represent hydrogen or chlorine;and Z represents. —CH₂—, —O— or —S—; said Formula (IV) includes (+)isomer, (−) isomer and (±) isomer]

[0042] and pharmaceutically acceptable acid addition salts thereof.

[0043] Among the compounds represented by Formula (IV),3-(1-pyrrolidinylmethyl)-4-[5,6-dichloro-1-indanecarbonyl]-tetrahydro-1,4-thiazineis preferred.

[0044] The opioid κ receptor agonist compounds represented by Formula(IV) may be produced by the method described in WO94/05646.

[0045] Preferred examples of opioid κ receptor agonist compound stillalso include the compounds represented by the following Formula (V):

[0046] [wherein X and Y independently represent hydrogen or chlorine;said Formula (V) includes (+) isomer, (−) isomer and (±) isomer]

[0047] and pharmaceutically acceptable acid addition salts thereof.

[0048] Among the compounds represented by Formula (V),2-(3,4-dichlorophenyl)-N-methyl-N-[1-phenhyl-2-(1-pyrrolidinyl)ethyl]acetamideis preferred.

[0049] The opioid κ receptor agonist compounds represented by Formula(V) may be produced by the method described in J. J. Barlow et al., J.Med. Chem., 34, 3149 (1991).

[0050] Examples of the pharmaceutically preferred acid addition salts ofthe opioid κ receptor agonist compounds represented by theabove-described Formulae (I) to (V) include inorganic acid salts such ashydrochloric acid salt, sulfuric acid salt, nitric acid salt,hydrobromic acid salt, hydriodic acid salt and phosphoric acid salt;organic carboxylic acid salts such as acetic acid salt, lactic acidsalt, citric acid salt, oxalic acid salt, glutaric acid salt, malic acidsalt, tartaric acid salt, fumaric acid salt, mandelic acid salt, maleicacid salt, benzoic acid salt and phthalic acid salt; and organicsulfonic acid salts such as methane sulfonic acid salt, ethane sulfonicacid salt, benzene sulfonic acid salt, p-toluene sulfonic acid salt andcamphor sulfonic acid salt. Among these, hydrochloric acid salt,hydrobromic acid salt, phosphoric acid salt, tartaric acid salt, methanesulfonic acid salt and the like are preferred, although, needless tosay, the acid addition salts are not restricted to these salts.

[0051] These opioid κ receptor agonist compounds may be orally orparenterally administered as they are or in the form of a pharmaceuticalcomposition after being admixed with a known pharmaceutically acceptablesalt, carrier, vehicle or the like.

[0052] As oral formulations, tablets and capsules may be employed. Asparenteral formulations in the form of an injection solution,percutaneous absorption preparation, tape, ointment, cream, stupe,liniment, patch, external solution, eye drop, ear drop or nasal drop mayalso be employed. These formulations may be prepared by the well-knownmethods usually employed in the field of pharmaceuticals.

[0053] The content of the opioid κ receptor agonist compound in apharmaceutical composition is not restricted, and may usually be, forexample, 0.1 μg to 100 mg in oral formulations, 0.01 μg to 10 mg ininjection solutions, and 0.001 ng/m² to 100 μg/m² per one application inpercutaneous or external preparations.

[0054] The administration dose may be appropriately selected dependingon the symptom, age and the like of the patient, and may usually be,about 0.1 μg to 100 mg for oral administration, and about 0.01 μg to 10mg for parenteral administration, in terms of the amount of theeffective component for per day per adult.

[0055] The disorders for which the therapeutic drug according to thepresent invention is to be applied are nervous disorders, particularly,RLS, PLM, myoclonic syndrome, contraction, painful contraction and thelike, especially restless legs syndrome.

EXAMPLE

[0056] The present invention will now be described more concretely byway of an example.

Example 1

[0057] A solution containing 10 μg of(−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β[N-methyl-trans-3-(3-furyl)acrylamide]morphinanhydrochloric acid salt 1

[0058] was encapsulated into a soft capsule made of gelatin to obtain anoral preparation. This oral preparation was administered to two patientswho had been diagnosed as restless legs syndrome. Both of the twopatients complained abnormal itchy sensation on the lower limbs andsleep is sometimes disturbed. By taking the oral preparation, theabnormal sensation disappeared 2 hours after taking the preparation inone patient, and 4 hours after taking the preparation in anotherpatient. In both of the two patients, the effect for eliminating theabnormal sensation continued at least for 24 hours, so that sleepdisturbance did not occur in the night and they could fallen asleep.Thus, it was recognized that the drug clearly had therapeutic effectagainst restless legs syndrome.

INDUSTRIAL AVAILABILITY

[0059] The therapeutic drug for psychoneurotic disorders according tothe present invention are useful for the therapies of nervous disorders,especially restless legs syndrome.

1. A therapeutic drug for psychoneurotic disorders comprising an opioidκ receptor agonist compound (excluding pentazocine) as an effectiveingredient.
 2. The therapeutic drug according to claim 1, wherein saidpsychoneurotic disorder is restless legs syndrome, periodic limbmovements accompanied by sleep, myoclonic syndrome or contraction. 3.The therapeutic drug according to claim 1 or 2, wherein said opioid κagonist compound is a morphinan represented by the following Formula(I):

[wherein . . . represents double bond or single bond; R¹ representsC₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂aryl, C₇-C₁₃ aralkyl, C₄-C₇ alkenyl, allyl, C₁-C₅ furan-2-yl-alkyl orC₁-C₅ thiophene-2-yl-alkyl; R² represents hydrogen, hydroxy, nitro,C₁-C₅ alkanoyloxy, C₁-C₅ alkoxy, C₁-C₅ alkyl or —NR⁹R¹⁰ wherein R⁹represents hydrogen or C₁-C₅ alkyl, and R¹⁰ represents hydrogen, C₁-C₅alkyl or —C(═O)R¹¹— wherein R¹¹ represents hydrogen, phenyl or C₁-C₅alkyl; R³ represents hydrogen, hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅alkoxy; A represents —XC(═Y)—, —XC(═Y)Z-, —X— or —XSO₂— (wherein X, Yand Z independently represent NR⁴, S or O; R⁴ represents hydrogen, C₁-C₅linear or branched alkyl or C₆-C₁₂ aryl, wherein R⁴s may be the same ordifferent); B represents valence bond, C₁-C₁₄ linear or branchedalkylene (with the proviso that said alkylene may have at least onesubstituent selected from the group consisting of C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,cyano, trifluoromethyl and phenoxy, and that 1 to 3 methylene groups maybe substituted by carbonyl group(s)), C₂-C₁₄ linear or branched acyclicunsaturated hydrocarbon containing 1 to 3 double bonds and/or triplebonds (with the proviso that said acyclic unsaturated hydrocarbon mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine,iodine, amino, nitro, cyano, trifluoromethyl and phenoxy, and that 1 to3 methylene groups may be substituted by carbonyl group(s)), or C₁-C₁₄linear or branched saturated or unsaturated hydrocarbon containing 1 to5 thioether bonds, ether bonds and/or amino bonds (with the proviso thathetero atom does not directly bind to A, and 1 to 3 methylene groups maybe substituted by carbonyl group(s)); R⁵ represents hydrogen or anorganic group having one of the following skeletons:

(wherein Q represents —NH—, —O— or —S—; T represents —CH₂—, —NH—, —S— or—O—; 1 represents an integer of 0 to 5; and m and n independentlyrepresent integers of not less than 0, the sum of m and n being not morethan 5) (with the proviso that the skeletons may have at least onesubstituent selected from the group consisting of C₁-C₅ alkyl, C₁-C₅alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine,amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxyand methylenedioxy); R⁶ represents hydrogen; R⁷ represents hydrogen,hydroxy, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, or R⁶ and R⁷ cooperativelyrepresent —O—, —CH₂— or —S—; and R⁸ represents hydrogen, C₁-C₅ alkyl orC₁-C₅ alkanoyl; said Formula (I) includes (+) isomer, (−) isomer and (±)isomer] or a pharmaceutically acceptable acid addition salt thereof. 4.The therapeutic drug according to claim 3, wherein in said Formula (I),R¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl,benzyl or phenethyl; R² and R³ are independently hydrogen, hydroxy,acetoxy or methoxy; A represents —XC(═Y)— (wherein X represents NR⁴, Sor O; Y represents O and R⁴ represents hydrogen or C₁-C₅ alkyl),—XC(═Y)Z-, —X— or —XSO₂— (wherein X represents NR⁴; Y represents O or S;Z represents NR⁴ or O; and R⁴ represents hydrogen or C₁-C₅ alkyl); B isC₁-C₃ linear alkylene; R⁶ and R⁷ cooperatively represent —O—; and R⁸ ishydrogen.
 5. The therapeutic drug according to claim 4, wherein in saidFormula (I), A represents —XC(═Y)— or —XC(═Y)Z- (wherein X representsNR⁴; Y represents O; Z represents O; and R⁴ represents C₁-C₅ alkyl). 6.The therapeutic drug according to any one of claims 3 to 5, wherein insaid Formula (I), R⁵ represents hydrogen or an organic group having oneof the following skeletons:

(wherein Q represents —O— or —S—) (with the proviso that the skeletonsmay have at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy).
 7. Thetherapeutic drug according to claim 6, wherein in said Formula (I), Arepresents —XC(═Y)— or —XC(═Y)Z- (wherein X represents NR⁴; Y representsO; Z represents O; and R⁴ represents C₁-C₅ alkyl).
 8. The therapeuticdrug according to claim 3, wherein in said Formula (I), R¹ is methyl,ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl orphenethyl; R² and R³ are independently hydrogen, hydroxy, acetoxy ormethoxy; A represents —XC(═Y)— (wherein X represents NR⁴; Y representsO; and R⁴ represents C₁-C₅ alkyl); B is —CH═CH—, —C≡C—, —CH₂O— or—CH₂S—; R⁶ and R⁷ cooperatively represent —O—; and R⁸ is hydrogen. 9.The therapeutic drug according to claim 8, wherein in said Formula (I),R⁵ represents hydrogen or an organic group having one of the followingskeletons:

(wherein Q represents —O— or —S—) (with the proviso that the skeletonsmay have at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy).
 10. Thetherapeutic drug according to claim 8, wherein in said Formula (I), B is—CH═CH— or —C≡C—.
 11. The therapeutic drug according to claim 10,wherein in said Formula (I), R⁵ represents hydrogen or an organic grouphaving one of the following skeletons:

(wherein Q represents —O— or —S—) (with the proviso that the skeletonsmay have at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy).
 12. Thetherapeutic drug according to claim 1 or 2, wherein said opioid κreceptor agonist compound is represented by the following Formula (II):

[wherein R represents two hydrogen atoms or —O—CH₂CH₂CH₂—; Ar represents

(wherein X and Y independently represent hydrogen or chlorine) or

(wherein Z represents O or S); said Formula (II) includes (+) isomer,(−) isomer and (±) isomer] or a pharmaceutically acceptable acidaddition salt thereof.
 13. The therapeutic drug according to claim 1 or2, wherein said opioid κ receptor agonist compound is represented by thefollowing Formula (III):

[wherein X represents hydrogen, chlorine or trifluoromethyl; Yrepresents hydrogen or chlorine; and Z represents —CH₂—, —OCH₂ CH₂O— or═NCO₂ CH₃; said Formula (III) includes (+) isomer, (−) isomer and (±)isomer] or a pharmaceutically acceptable acid addition salt thereof. 14.The therapeutic drug according to claim 1 or 2, wherein said opioid κreceptor agonist compound is represented by the following Formula (IV):

[wherein X and Y independently represent hydrogen or chlorine; and Zrepresents —CH₂—, —O— or —S—; said Formula (IV) includes (+) isomer, (−)isomer and (±) isomer] or a pharmaceutically acceptable acid additionsalt thereof.
 15. The therapeutic drug according to claim 1 or 2,wherein said opioid κ receptor agonist compound is represented by thefollowing Formula (V):

[wherein X and Y independently represent hydrogen or chlorine; saidFormula (V) includes (+) isomer, (−) isomer and (±) isomer] or apharmaceutically acceptable acid addition salt thereof.
 16. Use of anopioid κ receptor agonist compound (excluding pentazocine) for theproduction of a therapeutic drug for psychoneurotic disorders.
 17. Useof said compounds or the pharmaceutically acceptable acid addition saltsthereof according to any one of claims 3 to 15 for the production of atherapeutic drug for psychoneurotic disorders.
 18. The use according toclaim 16 or 17, which is a therapeutic drug for restless legs syndrome.19. A method of therapy for psychoneurotic disorders, comprisingadministering an effective amount of an opioid κ receptor agonistcompound (excluding pentazocine).
 20. A method of therapy forpsychoneurotic disorders, comprising administering an effective amountof said compound or the pharmaceutically acceptable acid addition saltthereof according to any one of claims 3 to
 15. 21. The method accordingto claim 19 or 20, wherein said psychoneurotic disorder is restless legssyndrome, periodic limb movements accompanied by sleep, myoclonicsyndrome or contraction.